rs1555523076

chr16-46662991-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_018206.6(VPS35):c.1819A>G(p.Met607Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VPS35 NM_018206.6 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.79

Genes affected

VPS35 (HGNC:13487): (VPS35 retromer complex component) This gene belongs to a group of vacuolar protein sorting (VPS) genes. The encoded protein is a component of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. The close structural similarity between the yeast and human proteins that make up this complex suggests a similarity in function. Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, VPS35

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS35	NM_018206.6	c.1819A>G	p.Met607Val	missense_variant	14/17	ENST00000299138.12
VPS35	XM_011523227.4	c.1732A>G	p.Met578Val	missense_variant	14/17
VPS35	XM_005256045.4	c.1618A>G	p.Met540Val	missense_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS35	ENST00000299138.12	c.1819A>G	p.Met607Val	missense_variant	14/17	1	NM_018206.6	P1
VPS35	ENST00000568784.6	c.*2489A>G		3_prime_UTR_variant, NMD_transcript_variant	14/17	1
VPS35	ENST00000562420.1	n.457A>G		non_coding_transcript_exon_variant	2/4	2
VPS35	ENST00000647959.1	c.*1882A>G		3_prime_UTR_variant, NMD_transcript_variant	15/18

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Parkinson disease 17 Other:1

not provided, no classification provided

literature only

GeneReviews

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	22
Dann	Benign	0.91
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.0086
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.28
Sift	Benign	0.49	T
Sift4G	Benign	0.26	T
Polyphen		0.030	B
Vest4		0.74
MutPred		0.64		Loss of phosphorylation at Y604 (P = 0.2673);
MVP		0.71
MPC		0.50
ClinPred		0.53	D
GERP RS		5.5
Varity_R		0.45
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555523076; hg19: chr16-46696903;